Abstract P5-02-38: Leptin receptor (Ob-R)/leptin axis significantly modulates tumour-infiltrating lymphocytes (TILs) and PD-1 expression in early HER2+ breast cancer (BC) emerging as a new surrogate marker for immunotherapy
Authors: Laura García-Estévez, Adela Fernández, José Palacios, Miguel Sampayo, Isabel Calvo, Eva Díaz, Marta González, Belén Pérez-Míes, Silvia González, José Manuel Pérez-García, Javier Cortés, Gema Moreno-Bueno
Journal: Cancer Research (2023)

Abstract Leptin receptor (Ob-R)/leptin axis significantly modulates tumour-infiltrating lymphocytes (TILs) and PD-1 expression in early HER2+ breast cancer (BC) emerging as a new surrogate marker for immunotherapy. Background: There is strong pre-clinical evidence that obesity produces T-cell dysfunction and high PD-1 expression resulting in a paradoxical benefit from immunotherapy. This effect is driven, at least in part, by leptin that exerts its action through binding Ob-R, which is known to be highly expressed in HER2+ BC. TILs correlate with pathological response and long-term outcomes in BC; however the precise mechanism by which these T-cells are activated in and around tumour remains partially unknown. The primary aim of this study was to investigate the role of Ob-R/leptin axis in modulating TILs and PD-1 expression and its effect in pathological response in early HER2+ BC patients who have received neoadjuvant systemic treatment (NST). Methods: Women with HER2+ BC receiving anti-HER2-based NST followed by surgical resection were evaluated. Patient’s height and weight were measured before NST to calculate the body mass index (BMI). Based on the IHC results in diagnostic biopsy, tumors were categorized as HER2+/HR+ and HER2+/HR-. Ob-R expression was routinely measured in the diagnostic biopsy using the BOND RX Research Platform (Leica Biosystems). The Ob-R was classified as over-expressed if there were more than 50% positive cells with weak or strong staining. TILs and PD-1 expression were scored centrally in pre-treatment biopsy. TILs were considered as binary, &amp;lt; 30.0% versus ≥30.0% and PD-1 positive (&amp;gt;1%). Associations with pathological complete response (pCR; ypT0/isN0) were assessed using chi-squared or Wilcoxon test. Results: Of the 74 HER2+ BC patients included in the study, 47 (63.5%) had over-expression of Ob-R, 26 (35.1%) were overweight/obese (BMI ≥25kg/m2), and 42 (56.8%) had pCR status. Ob-R expression was similar regardless of menopausal status, age or HR expression. Patients with Ob-R overexpressed were 21 (80.8%) of 26 with BMI ≥25kg/m2 versus 26 (54.2%) of 48 with BMI &amp;lt; 25Kg/m2 (p=0.023). Tumors with Ob-R overexpressed had significantly higher mean levels of TILs than those with non-overexpressed Ob-R (21.4% [IQR, 7.5-30] vs 12.4% [IQR, 5-10]; p=0.009). Despite higher rates of TILs, the rate of pCR in Ob-R overexpressed tumours (57.4% [27 of 47 patients]) was not higher than in non-overexpressed tumours (55.6% [15 of 27 patients]; p=0.874). This could be due to the fact that Ob-R-overexpressed tumours had a significant higher median PD-1 expression than Ob-R-negative tumours (2% [IQR, 0.5-7.5] vs 0% [IQR, 0-1]; p&amp;lt; 0.001). Finally, no differences were found in terms of Ob-R expression and pathological response by hormone receptor expression. Conclusions: This multidisciplinary clinical study decodes for the first time how obesity, through the OB-R/leptin axis, might activate TILs but apparently dysfunctional as it is not translated into higher pCR; probably due to the presence of exhausted features such as high PD-1 expression. The role of Ob-R together with PD-1 as a potential biomarker for immunotherapy should be further explored. Citation Format: Laura García-Estévez, Adela Fernández, José Palacios, Miguel Sampayo, Isabel Calvo, Eva Díaz, Marta González, Belén Pérez-Míes, Silvia González, José Manuel Pérez-García, Javier Cortés, Gema Moreno-Bueno. Leptin receptor (Ob-R)/leptin axis significantly modulates tumour-infiltrating lymphocytes (TILs) and PD-1 expression in early HER2+ breast cancer (BC) emerging as a new surrogate marker for immunotherapy. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-38.